The TRIM5 gene encodes TRIM5a, a cytosolic protein that confers intrinsic resistance to retroviral infection. Since the initial description of the antiretroviral activity of TRIM5a, over one hundred related publications have appeared in the primary, peer-reviewed AIDS literature. However, these studies have focused almost exclusively on structure/function studies of TRIM5's antiviral mechanism in tissue culture based assays. Thus, surprisingly little is known about the regulation, mechanisms of suppression or downstream consequences of TRIM5 expression in vivo. Critically, published reports from our lab and at least one other group demonstrate a significant impact of TRIM5 expression on SIV infection in macaque models of AIDS. Moreover, polymorphic variation in rhesus macaque TRIM5 remains as a formidable obstacle to a true animal model of HIV-1 infection and disease. This raises several crucial questions with direct relevance to HIV/AIDS and with specific practical implications for experimental models of AIDS. Finding answers to these questions is essential to understanding both the fundamental in vivo biology of TRIM5 and its specific relevance to preclinical AIDS research. The research plan is based on published data from our laboratory describing functional polymorphism in the rhesus macaque TRIM5 locus, and its influence on SIV infection. We propose three specific aims, designed to 1) fully assess the impact of TRIM5-mediated suppression on lentiviral infection and disease progression (first Specific Aim); 2) determine whether IFN-inducible TRIM5 gene expression is specifically altered by SIV infection (second Specific Aim); and 3) generate rationally designed HIV-1 strains capable of robust replication in primary cells of rhesus macaques representing all common TRIM5 genotypes (third Specific Aim). Specific Aim 1 and Specific Aim 2 will lead to a better understanding of TRIM5 in a biologically relevant, in vivo context, while work on Specific Aim 3 represents a critical but necessary step in the direction of a practical animal model of HIV-1 infection. Together, work on these three aims will illuminate the biological relevance of TRIM5- mediated suppression and lead to improved animal models of AIDS.